1. Field
This invention is in the field of methods for diagnosis of disease conditions and particularly diagnosis of pancreatic cancer and other gastrointestinal disease conditions.
2. State of the Art
Pancreatic cancer is a deadly disease which has a mortality rate in the United States of more than 27,000 people a year, Lillemoe, K. D., C. J. Yeo, and J. L. Cameron, Pancreatic cancer: state-of-the-art care. C A Cancer J Clin, 2000. 50(4): p. 241-68. About 85% of those diagnosed with the disease have metastasis or spread of the disease beyond the pancreas and are almost impossible to cure with surgical resection, the only possible method of curing the disease at this time. If the growth is found sooner it may be resected with a much better hope of cure. Only about 15% of the newly diagnosed cases are resectable and the chances of a cure are usually 25% or less. Wiesenauer C. A. et al., Preoperative Predictors of Malignancy in Pancreatic Intraductal Papillary Mucinous Neoplasms. Arch. Surg; 2003 138: p 610-618; Ros, P. R. and K. J. Mortele, Imaging features of pancreatic neoplasms. Jbr-Btr, 2001. 84(6): p. 239-49; Ryu, B., et al., Relationships and differentially expressed genes among pancreatic cancers examined by large-scale serial analysis of gene expression. Cancer Res, 2002. 62(3): p. 819-26; Ito, M., et al., Molecular basis of T cell-mediated recognition of pancreatic cancer cells. Cancer Res, 2001. 61(5): p. 2038-46. Earlier diagnosis is the only hope of allowing earlier successful treatment of pancreatic cancer at this time.
Since the dividing time of the pancreatic cancer cell is around 40 days, the cancer has been present for many months or years before it is detectable by present imaging and other diagnostic methods. Pathway markers have not as yet proved successful in the early diagnosis of pancreatic or other cancers with a high degree of specificity or sensitivity. Lillemoe, K. D., C. J. Yeo, and J. L. Cameron, Pancreatic cancer: state-of-the-art care. C A Cancer J Clin, 2000. 50(4): p. 241-68; Rosty C, Goggins M., Early detection of pancreatic carcinoma. Hematol Oncol Clin North Am, 2002 16(1):37-52.
With the development of tumors, dendritic cells or macrophages note new growth, whether of genetic or epigenetic origin, by recognizing the altered proteins presented on the cancer cell's surface through their receptor channels. The dendritic cells convey these altered protein changes to the lymphocytes with the addition of major histocompatibility complexes. This includes T. lymphocytes CD8 with HCS I and CD4 with HCS II. The B lymphocytes are subsequently programmed by the recognizing T lymphocyte. Zeng, G., MHC Class II-Restricted Tumor Antigens Recognized by CD4+T Cells: New Strategies for Cancer Vaccine Design. J Immunother, 2001. 24(3): p. 195-204; Jonuleit, H., et al., Identification and functional characterization of human CD4(+)CD25(+) T cells with regulatory properties isolatedfrom peripheral blood. J Exp Med, 2001. 193(11): p. 1285-94; Serbina N. V., Pamer E. G. Giving Credit Where Credit Is Due. Science, 2003, 301:1856-1857; and Baxevanis, C. N., et al., Tumor-specific CD4+T lymphocytes from cancer patients are required for optimal induction of cytotoxic T cells against the autologous tumor. J Immunol, 2000. 164(7): p. 3902-12. Through this mechanism, the lymphocytes specifically recognize the new growth and program specifically against it, sending tumor infiltrating lymphocytes or TIL cells to the new growth. These TIL cells may decrease in the area of the tumor as tolerance for the tumor develops. Ryschich, E., et al., Transformation of the microvascular system during multistage tumorigenesis. Int J Cancer, 2002. 97(6): p. 719-25. It has been shown that the CD4-CD25 T lymphocytes contribute to tolerance of developing cancer. Liyanage, U. K., et al., Prevalence of regulatory T cells is increased in peripheral blood and tumor microenvironment of patients with pancreas or breast adenocarcinoma. J Immunol, 2002. 169(5): p. 2756-61. The use of peripheral blood lymphocytes for diagnosis of certain diseases have been proposed and described in Hong M H, X. X., Mai H Q, Cao S M Min H Q, Analysis of gene expression patterns of periphery lymphocytes in patients with nasopharyngeal carcinoma. Ai Zheng, 2002. 21(1): p. 21-4; Xu T et al Microarray analysis reveals differences in gene expression of circulating CD8+ T cells in melanoma patients and healthy donors. Cancer Res. 2004 May 15; 64(10):3661-7; Thomas A M et al. Mesothelin-specific CD8(+) T cell responses provide evidence of in vivo cross-priming by antigen-presenting cells in vaccinated pancreatic cancer patients. J Exp Med. 2004 Aug. 2; 200(3): 297-306; and McLaren P J et al Antigen-specific gene expression profiles of peripheral blood mononuclear cells do not reflect those of T-lymphocyte subsets. Clin Diagn Lab Immunol. 2004 September; 11(5):977-82. Twine & Burczynski. Twine N C, et al. Disease-associated expression profiles in peripheral blood mononuclear cells from patients with advanced renal cell carcinoma. Cancer Res. 2003 Sep. 15; 63(18):6069-75. Burczynski M E, Twine N C et al. Transcriptional profiles in peripheral blood mononuclear cells prognostic of clinical outcomes in patients with advanced renal cell carcinoma. Clinical Cancer Res. 2005 Feb. 1; 11(3):1181-9.